Terpenes are bio-active compounds and there are numerous reports in the literature concerning their effects as antibacterial, antifungal, antihelminthic and antimitotic agents. Various terpenes are used in agriculture for growth inhibition, growth promotion and in the food industry as flavourings and fragrances. Interest in the potential for using terpenes in medical applications is increasing.
Lice have three stages in their lift cycle: egg, nymph (young), and adult. Newly hatched nymphs are identical in appearance to their parents except for the 2nd instar (nymph) which is smaller and has undeveloped reproductive organs. Nymphs gradually develop into adults, periodically shedding their skin (moulting) during the process. The life cycle (egg to egg) takes approximately 15 to 35 days during which time a female may lay between 50 and 150 eggs. Lice spend their entire life as ectoparasites on humans and, unlike other insects, they have a relatively consistent environment. Their close contact with human skin ensures favourable temperatures of 82.degree. F. to 86.degree. F., and an abundant food supply. Lice do not abandon their hosts unless the body temperature substantially changes due to death or high fever. Once dislodged from a person's body or clothing, they will infest a new human host in the immediate proximity. If a new host is not found within one to eight days, lice will starve to death.
During feeding, lice inject saliva into the skin of the host and this causes irritation and subsequent itching. Children under 12 years are more sensitive to louse feeding than other age groups. Scratching louse bite areas frequently causes an abrasion, which may become infected with other micro-organisms. Prolonged louse infestation causes a hardening and pigmentation of the skin known as "vagabond's disease".
Even though people experience unpleasant sensations as a result of louse infestation, they often deny pediculosis because of feelings of disgust and shame. Lice infestation used to be thought of as a problem only of the poor or poorly housed. It is now abundantly clear that the problem of head lice has extended to very large number of middle class homes in the western world and this leads to increasing numbers of consultations with family practitioners or pharmacists who advise as to the treatment currently being recommended.
Lice are spread through sharing contaminated clothing, hats, scarves, combs, hair brushes, and other headgear, or as a result of close physical contact with an infected person. Other occasional sources are bedding, furniture, rugs and floor surfaces where dislodged lice may be present.
Once infested, an individual usually carries a few dozen lice. However, some people have been known to carry several hundred lice and on rare occasions, one to two thousand lice. Human lice do not normally infest pets and domestic animals.
Of the three species of lice, only body lice have been known to transmit disease organisms. Relapsing fever, typhus, and trench fevers were transmitted by body lice in Europe during World Wars 1 and 2 and the Naples Typhus Epidemic of 1944 was brought under control using DDT to kill lice--one of the earliest widespread uses of this insecticide.
Head lice (Pediculosus humanus capitus), are by far the most common and troublesome of the human lice infestations and in the US, alone, between 8 and 12 million children have head lice at any one time.
"Nits" is the term used to describe the small yellowish-white, oval-shaped eggs cases of head lice that are `glued` at an angle to the side of a hair shaft near its base. Favourite sites are behind the ears or on the nape of the neck. Eggs are laid by a mature female louse and after hatching; feeding starts immediately; this activity causes the young head lice to rapidly develop a reddish-brown colour. Development takes about 18-20 days and the adult can live for about one month, during which time each female lays between 50 and 150 eggs at the rate of 4 to 6 per day, usually at night. The eggs are cylindrical, yellowish-white, and about 0.8 mm long. Feeding occurs at fairly frequent intervals and at least twice daily. The adult male is about 2.1 mm long and the female rather larger, about 3 mm long. Mating occurs within 10 hours of maturation and recurs quite frequently during the remainder of life. Head lice can survive three to four days if dislodged from the host.
Head lice are transferred from one infected person to another through physical contact and the communal use of combs, hair brushes, head apparel, towels, bedding, and personal clothing.
Feeding activity irritates the scalp, causing intense itching. Head lice are not known to transmit any disease organisms directly but a secondary infection may result if the skin is broken by repeatedly scratching the area. In severe infestations the hair may become matted as a result of exudates from louse bites.
The impact of being publicly identified as having lice (for instance in a school classroom) can be distressing and socially embarrassing. Children, particularly those of primary/first school age, are most likely to get head lice because of their close contact and social interactions with each other which creates numerous opportunities for lice to be spread amongst them. Children who become infested in school will carry lice home and may infest family members who unknowingly become a source for recurring louse problems in the home. Few parents react with total equanimity to the discovery.
The body louse or cootie (Pediculosus humanus humanus), is very similar to the head louse in physical appearance except that it is 10%-20% percent larger. This insect is generally associated with unclean environments where inadequate bathing occurs or clothes are shared. The body louse lives on clothing that comes in close contact with the human body, such as the waistline and crotch of trousers, shirt armpits and collars and underwear, rather than the body itself which it visits only to obtain a blood meal.
The life cycle of the body louse is, in many respects, similar to that of the head louse. However, in this louse, the fertilised female adult lays nine to ten eggs per day, and may lay 270 to 300 eggs in her lifetime. The eggs are usually glued to fibres of clothing, often in the seams. Eggs hatch in six to nine days. Newly hatched nymphs begin to suck blood at once and feed frequently during day or night, especially when the host is quiet. Nymphs mature to adults in approximately 16 to 18 days, during which process three moultings occur. Newly emerged adult males, 2.3 mm long, and females, 4.2 mm long, mate within a day. The female begins laying eggs one or two days after reaching maturity. The life cycle (egg to egg) is completed in 22 to 28 days. The adults are greyish white, and live approximately 30 to 40 days. After discontinued contact with the host, body lice can survive 8 to 10 days. They spread through contact with infested persons or their clothing.
This crab or pubic louse has a crab-like appearance and is greyish white. Although formerly grouped within the genus Pediculus they are now more correctly classified as Pthirus pubis (syn. Pediculus pubis). They infest the pubic region of the body but in severe infestations may be found in armpits, moustaches, beards, eyelashes and eyebrows.
Fertilised adult females lay three eggs per day and a total of 26 eggs in their lifetime. The oval, whitish eggs, 1/50 inch long, are glued to coarser hair near the skin. The eggs hatch after six to eight days. The newly hatched nymphs start sucking blood immediately. The nymphs grow into adults after moulting three times in 15 to 17 days. The life cycle (egg to egg) is completed in 34 to 41 days. The adults are 1.6 mm long and live for a month on the human host. If they are dislodged, they survive less than 24 hours.
Both nymphs and adults tend to settle on one spot, and feeding continues intermittently for hours or days. Spread is through intimate physical contact, particularly sexual contact and possibly also through infested bedding, clothing and toilet seats.
In theory, elimination of head lice in an infested family should be relatively straightforward. Advice is readily available in schools and GP surgeries in Western countries. Reporting to school authorities is strongly encouraged but many parents evade the issue because of shame or embarrassment. Failure to report, coupled with lack of awareness that the problem exists or reluctance to deal with it at all, are the primary reasons for reinfestation in the school and community environments. Trained school staff, especially a nurse if there is one, do carry out inspections but often encounter difficulties with parents who adopt a state of denial.
The extent of delousing activities in a school depends on a variety of factors such as the age of the students and general resources. Difficult schools in inner city areas are particularly prone to the problem and have, in general, the least resources and also the least co-operative parent population. It is rare for schools, other than some residential schools, to treat head lice infestation actively. Once infestation is recognised in a group, the classic steps are to encourage inspection of the whole group and all of their family members, to encourage higher standards of personal hygiene and to institute pesticide treatment with chemicals. This tends to be applied as a lotion or conditioner which must be left for a specified dwell-time to be effective. The use of special combs which can remove both live lice and their eggs is also encouraged. The action of combing correctly is considered to help the problem by breaking the legs of the lice. It is also being recommended that hair is over-conditioned with a standard product as this makes it difficult for the lice to grip the hair shaft. In the case of pubic lice, transmitted by sexual contact, it is particularly important that the sexual partner(s) should be treated simultaneously to avoid reinfestation.
Other general recommendations include machine washing in hot water (over 54.degree. C.) or dry cleaning all clothing, including coats, hats, scarfs, pillow cases, towels, and bedding materials, which may have contacted an infested individual.
Most mediated shampoos and lotions for treating head lice are available over the counter, through some require a prescription. Widely used products in the OTC category in the USA include Rid.RTM. Lice Killing Shampoo (Pfizer), Nix.RTM. Creme Rinse and A-2000.RTM. Shampoo Concentrate which contains pyrethrins and piperonyl butoxide as the active ingredients (AI).
Prescribable US brands include Kwell.RTM., (containing lindane 1%, as the active) and Ovidem.RTM., (active ingredient 0.5% malathion).
In the U.K. the treatments for lice have recently received negative press at tention (Sunday Times Oct. 5, 1997 and World In Action, documentary TV programme, Channel 3, Independent TeleVision) and despite the fact that the press focussed on malathion (Derbac-M.TM., Prioderm.TM. and Suleo-M.TM.; marketed in the UK by Seton Healthcare) there has been a knock-on effect and lice products generally are being increasingly thought of with caution. The key concerns are regarding the use of organo phosphates and their associated toxicity, especially as they are so often used in young children. Malathion toxicity includes nausea, vomiting, diarrhoea, broncho-constriction, blurred vision, excessive salivation, muscle twitching, cyanosis, convulsions, coma and respiratory failure. Against this background it may be somewhat surprising that its topical use was not more closely monitored earlier. Even permethrin (the active in Lyclear.TM.) has to be used with caution and must not be used in an enclosed space. It must also be kept away from pets and fish of known direct toxicity in those species.
Pediculicides, selectively kill lice which invade the epidermis. Although a number of brands contain either carbaryl or malathion, lotions containing phenothrin and permethrin and now the major products. These are pyrethroid compounds and are highly effective insecticidal neurotoxins, with efficacy against both adult lice and their eggs. Permethrin (3-phenoxyphenyl) methyl (+/-) cis/trans 3-(2,2-dichloroethenyl) 2,2-dimethylcyclopropanecarboxylate, is used as a 0.5% preparation in a paraffin base. Other actives are benzyl benzoate and crotamiton. All are applied topically. The manufactures claim appropriate use does not lead to resistance but evidence now to hand would seem to suggest otherwise. Indeed, local UK Health Authorities (through directives issued to GPs, school nurses and health visitors) advise alternation of products within a co-ordinated national policy. Many Health Authorities are now advising no active treatment because of problems apparently due to resistant lice. Instead they recommend over-conditioning the hair and regular use of a specially designed lice comb.
The main brands used in the U. K. are Lyclear.TM. Creme Rinse Warner Lambert--a lotion conditioner applied after shampooing and left for 10 minutes and Full Marks.TM. (phenothrin) Seton Healthcare a lotion rubbed into the hair and left for 2 hours. These 2 products are prescribable but also available over-the-counter. Lyclear.TM. appears to be the clear market leader. All prior art anti-head lice preparations have the drawback of requiring significant dwell-times on the scalp and this is negative for the products because it reduces user-compliance and encourages misues. Both tendencies reduce the success rate in clearing lice. Manufacturers claim that resistance is not an issue and that treatment failures are due to incorrect use. However, this does clearly indicate that these agents are not user friendly.
The issue of efficacy of prior art preparations, used to control head lice, is important and in this context, a report by Vander Stichele R. H. et al, from the Heymans Institute of Pharmacology, University of Ghent, Belgium entitled `Systematic review of clinical efficacy of topical treatments for head lice.` (BMJ Sep. 2, 1995. p604-8), is relevant. The group sought to collect and evaluate all trials on clinical efficacy of topical treatments for head lice. They undertook a systematic review of randomised trials identified from the data sources Medline, International Pharmaceutical Abstracts, Science Citation Index, letters to key authors and companies and hand search of journals. All the trials reviewed were carried out in schools or communities in patients infested with lice. The main outcome measure, which the Review Group were concerned with, was cure rate (absence of live lice and viable nits) on day 14 after treatment. A total of 28 trials were identified and evaluated according to eight general and 18 lice-specific criteria. Of the 14 trials rated as having low to moderate risk of bias, seven were selected because they used the main outcome measure. These seven trials described 21 evaluations of eight different compounds and placebo (all but two evaluations were of single applications). Only permethrin 1% creme rinse showed efficacy in more than two studies with the lower 95% confidence limit of cure rate above 90%. The authors' conclusion was that "only for permethrin has sufficient evidence been published to show efficacy. Less expensive treatments such as malathion and carbaryl need more evidence of efficacy. Lindane (1,2,3,4,5,6-Hexachloro-cyclohexane) and the natural pyrethrines are not sufficiently effective to justify their use". In addition, many health authorities and registration agencies regard lindane, which is used as a scabicide, pediculicide and insecticide, as dangerous.
It is tempting to speculate that the mechanism of resistance might be similar to that which arise with certain bacteria--a sub-lethal dose is repeatedly administered and engenders acquired resistance.
In the USA there are also products available for treating bedding, clothing and furniture including Lice Treatment Kit.TM. (active ingredient: resmethrin 0.5%), R & C Spray.TM. (active ingredient: phenothrin 0.382%) and Rid.RTM. Lice Control Spray (active ingredient: permethrin 0.5%). These products are available from stores rather than pharmacies and so far as is known, there are no equivalent products available in the UK.
Thus there is a significant need for a treatment for this widespread and troublesome problem which would address the issues which detract from the prior art products. An ideal product might offer no dwell time in excess of that for ordinary shampoos used by non-infested individuals, absence of toxicity, user friendly presentation and resistance-free mode of action.
The following US patents are considered relevant:
U.S. Pat. No. 5,635,174; U.S. Pat. No. 4,927,813; U.S. Pat. No. 4,379,168; U.S. Pat. No. 5,411,992; U.S. Pat. No. 5,591,435; U.S. Pat. No. 4,933,371; U.S. Pat. No. 5,627,166. PA1 BMJ Nov. 18, 1995; 311(7016):1369; discussion 1369-70 PA1 Comment in: BMJ Jan. 13, 1996;312 (7023): discussion 123. PA1 Co-operative Extension, Institute of Agriculture and Natural Resources, University of Nebraska, Lincoln, PA1 Larousse Encyclopaedia of Animal Life Vander Stichele R. H. et al. Systematic review of clinical efficacy of topical treatment for head lice. BMJ Sep. 2, 1995. p604-8. PA1 Redistilled limonene PA1 Beta-ionone PA1 Linalool PA1 Geraniol PA1 Eugenol PA1 Myrcene PA1 Carvone.
Other documents considered relevant are: